The modulation by chlormethiazole of the GABA A ‐receptor complex in rat brain

Self Cite

107

The effect of chlormethiazole, and other drugs which potentiate γ‐aminobutyric acid (GABA) function on delayed neuronal death in the hippocampus has been examined in the gerbil. Chlormethiazole (100 mg kg−1, i.p.) and two other drugs previously reported to be neuroprotective (dizocilpine, 3 mg kg−1, i.p. and ifenprodil, 4 mg kg−1, i.p.) were all found to prevent neurodegeneration of CA1/CA2 neurones in the hippocampus when given 30 min before a 5 min episode of bilateral carotid artery occlusion. Chlormethiazole (100 mg kg−1) was neuroprotective when given up to 3 h, after the ischaemic episode. Given 1 h after the cartoid artery occlusion, chlormethiazole produced significant protection against hippocampal neurodegeneration at a dose of 50 mg kg−1, but not at 25 mg kg−1. Phenobarbitone (100 mg kg−1, i.p.) and Saffan (alphaxalone, 45 mg kg−1plus alphadalone, 15 mg kg−1, i.p.) were not protective when given 1 h after the ischaemic episode while pentobarbitone (30 mg kg−1, i.p.) had a modest protective effect. Evidence is presented to show that neither the operating procedure nor the chlormethiazole administration lowered rectal or cerebral temperature. The data suggest that chlormethiazole may be a useful treatment in the prevention of neurodegeneration following stroke or cardiac arrest.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil

Cross¹,

Jones²,

Baldwin³

et al. 1991

Self Cite

107

“…We also examined the e ects of clomethiazole and pentobarbitone, two compounds that potentiate GABA A receptor function. Both bind to related ± but not identical ± sites associated with the chloride channel of the GABA A receptor ionophore complex (Cross et al, 1989;Moody & Skolnick, 1989;Green et al, 1996;Zhong & Simmonds, 1997). Neuroprotection studies have highlighted functional di erences between these two drugs.…”

Section: Discussionmentioning

confidence: 99%

On the regulation of ischaemia‐induced glutamate efflux from rat cortex by GABA; in vitro studies with GABA, clomethiazole and pentobarbitone

Nelson

Green

Lambert

et al. 2000

1 Prisms of adult rat cortex were maintained in vitro in either aerobic conditions (control) or conditions simulating an acute ischaemic challenge (hypoxia with no added glucose). 2 Endogenous glutamate e ux increased with time in ischaemic conditions, being 2.7 fold higher than control e ux at 45 min. Returning prisms to control solution after 20 min of simulated ischaemia resulted in glutamate e ux returning to near-control values. Endogenous GABA e ux in ischaemic conditions also increased, being 4.5 fold higher than control e ux at 45 min. 3 Ischaemia-induced glutamate e ux was not accompanied by increased lactate dehydrogenase e ux and was unaltered by omitting calcium from the extra-cellular solution and adding EGTA (0.1 mM). 4 Both GABA and the GABA-mimetic clomethiazole inhibited ischaemia-induced glutamate e ux, with IC 50 values of 26 and 24 mM respectively. The maximum inhibition by either drug was 60 ± 70%. Bicuculline (10 mM) abolished the inhibitory e ect of GABA (100 mM) but not clomethiazole (100 mM). Picrotoxin (100 mM) abolished the action of both GABA and clomethiazole. 5 Pentobarbitone inhibited glutamate e ux at 100 ± 300 mM (maximal inhibition: 39%). Bicuculline (10 mM) abolished this e ect. 6 These data suggest that ischaemia-induced glutamate e ux from rat cerebral cortex is calciumindependent and not due to cell damage up to 45 min. The inhibitory e ect of GABA, clomethiazole and pentobarbitone on ischaemia-induced glutamate e ux appears to be mediated by GABA A receptors. The results suggest that clomethiazole, unlike pentobarbitone, is able to activate the GABA A receptor-linked chloride channel directly and not merely potentiate the e ect of endogenous GABA.

“…Thus, muscimol opens the channel by activation of the GABAA receptor (Curtis et al, 1971), the benzodiazepines bind to a specific site of the receptor complex and increase the frequency of the opening of the chloride channel (Study & Barker, 1981), barbiturates bind to another site and prolong the length of opening of the channel (Study & Barker, 1981) and chlormethiazole acts both by potentiating the effects of GABA and by modulating channel opening directly (Harrison & Simmonds, 1983;Moody & Skolnick, 1989;Cross et al, 1989). Elevation of the serum corticosterone concentration produced acutely by these compounds does not appear per se to be the cause of the counteraction of the tolerance to 8-OH-DPAT-induced corticosterone secretion, since picrotoxin also acutely increased the corticosterone level but potentiated the tolerance to 8-OH-DPAT.…”

Section: Discussionmentioning

confidence: 99%

Counteraction of the rapid tolerance to 8‐OH‐DPAT‐induced corticosterone secretion in rats by activation of the GABA_A receptor‐chloride channel complex

Kelder¹,

Ross²

1993

1 The effect of various classes of compounds on the rapidly developed tolerance to 8-hydroxy-2-(di-npropylamino)tetralin (8-OH-DPAT)-induced corticosterone secretion was examined.2 Compounds activating the y-aminobutyric acidA (GABAA) receptor-chloride complex, i.e. muscimol (3 mg kg-'), diazepam (5 mg kg-'), flunitrazepam (1 mg kg-'), sodium pentobarbitone (10-30 mg kg-') and chlormethiazole ethane disulphonate (50 mg kg-') counteracted the development of tolerance when injected before or simultaneously with, but not 15 min after 8-OH-DPAT. 3 At these doses the compounds produced an acute increase in serum corticosterone but had, with the exception of muscimol, no effect on the response to the challenge dose of 8-OH-DPAT 24 h later. Muscimol significantly decreased the response. 4 The GABAA chloride channel antagonist, picrotoxin (1 mg kg-', s.c.), but not bicuculline (1 mg kg-', i.p.) potentiated the development of tolerance to 8-OH-DPAT-induced corticosterone secretion.5 A number of compounds with widely differing pharmacological actions were examined and found to have no effect on the development of tolerance to 8-OH-DPAT-induced corticosterone secretion.